Population pharmacokinetics and dosing regimen optimization of tacrolimus in Chinese lung transplant recipients

Abstract

We aimed to develop a population pharmacokinetic model of tacrolimus in Chinese lung transplant recipients, and propose model based dosing regimens for individualized treatment. We obtained 807 tacrolimus whole blood concentrations from 52 lung transplant patients and genotyped CYP3A5*3. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. Monte Carlo simulations were employed to design initial dosing regimens. Tacrolimus pharmacokinetics was described by a one compartment model with first order absorption and elimination process. The mean estimated apparent clearance was 13.1 l/h with 20.1% inter subject variability in CYP3A5*3/*3 70kg patients with 30% hematocrit and voriconazole free therapy, which is lower than that in Caucasian(17.5 to 36.5 l/h). Hematocrit, postoperative days, tacrolimus daily dose, voriconazole cotherapy, and CYP3A5*3 genotype were identified as significant covariates for tacrolimus clearance. To achieve the target trough concentration (10 to 15 ng/ml) on the 8th day after transplantation, CYP3A5*1/*3 patients with voriconazole free cotherapy, a higher initial dosage than the current regimen of 0.04 mg/kg q12h should be recommened. Given the nonlinear kinetics of tacrolimus and large variability, population pharmacokinetic model should be combined with therapeutic drug monitoring to optimize individualized therapy.